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Original article

Vol. 145 No. 5152 (2015)

Cure of tuberculosis despite serum concentrations of antituberculosis drugs below published reference ranges

  • Monica Meloni
  • Natascia Corti
  • Daniel Müller
  • Lars Henning
  • Ursula Gutteck
  • Amrei von Braun
  • Rainer Weber
  • Jan Sven Fehr
DOI
https://doi.org/10.4414/smw.2015.14223
Cite this as:
Swiss Med Wkly. 2015;145:w14223
Published
13.12.2015

Summary

PRINCIPLES: Therapeutic target serum concentrations of first-line antituberculosis drugs have not been well defined in clinical studies in tuberculosis (TB) patients.

METHODS: We retrospectively investigated the estimated maximum serum concentrations (eCmax) of antituberculosis drugs and clinical outcome of TB patients with therapeutic drug monitoring performed between 2010–2012 at our institution, and follow-up until March 2014. The eCmax was defined as the highest serum concentration during a sampling period (2, 4 and 6 hours after drug ingestion). We compared the results with published eCmaxvalues, and categorised them as either “within reference range”, “low eCmax”, or “very low eCmax”.Low/very low eCmax-levels were defined as follows: isoniazid 2–3/<2 mg/l, rifampicin 4–8/<4 mg/l, rifabutin 0.2–0.3/<0.2 mg/l, ethambutol 1–2/<0.1 mg/l and pyrazinamide <20 mg/l.

RESULTS: Concentrations of antituberculosis drugs in 175 serum samples of 17 patients with TB were analysed. In 12 (71%) patients, multiple therapeutic drug monitoring samples were collected over time, in 5 (29%) patients only one sample was available for therapeutic drug monitoring. Overall, 94% of all patients had at least one low antituberculosis drug concentration. Overall, 64% of all eCmax levels were classified as “low” or “very low”. The eCmax was below the relelvant reference range in 80% of isoniazid, 95% of rifampicin, 30% of pyrazinamide, and 30% of ethambutol measurements. All but one patient were cured of tuberculosis.

CONCLUSIONS: Although many antituberculosis drug serum concentrations were below the widely used reference ranges, 16 of 17 patients were cured of tuberculosis. These results challenge the use of the published reference ranges for therapeutic drug monitoring.

References

  1. The Global Plan To Stop TB 2011-2015. Geneva, Switzerland: World Health Organization. 2011.
  2. Global tuberculosis control 2011. Geneva, Switzerland: World Health Organization. 2011.
  3. Lungenliga. Handbuch Tuberkulose. Switzerland, Bundesamt für Gesundheit BAG. 2011. German.
  4. Horne DJ, Hubbard R, Narita M, Exarchos A, Park DR, Goss CH. Factors associated with mortality in patients with tuberculosis. BMC Infect Dis. 2010;10:258.
  5. Organization WH. World Health Organization, Treatment Of Tuberculosis Guidelines. World Health Organization, Geneva, Switzerland 2009, Fourth Edition.
  6. Berning SE, Huitt GA, Iseman MD, Peloquin CA. Malabsorption of antituberculosis medications by a patient with AIDS. N Engl J Med. 1992;327(25):1817–8.
  7. Patel KB, Belmonte R, Crowe HM. Drug malabsorption and resistant tuberculosis in HIV-infected patients. N Engl J Med. 1995;332(5):336–7.
  8. Peloquin CA, MacPhee AA, Berning SE. Malabsorption of antimycobacterial medications. N Engl J Med. 1993;329(15):1122–3.
  9. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, et al. Malabsorption of rifampin and isoniazid in HIV-infected patients with and without tuberculosis. Clin Infect Dis. 2004;38(2):280–3.
  10. Tappero JW, Bradford WZ, Agerton TB, Hopewell P, Reingold AL, Lockman S, et al. Serum concentrations of antimycobacterial drugs in patients with pulmonary tuberculosis in Botswana. Clin Infect Dis. 2005;41(4):461–9.
  11. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, et al. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother. 2004;48(11):4473–5.
  12. Sahai J, Gallicano K, Swick L, Tailor S, Garber G, Seguin I, et al. Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. Annal Intl Med. 1997;127(4):289–93.
  13. Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs. 2002;62(15):2169–83.
  14. Narita M, Hisada M, Thimmappa B, Stambaugh J, Ibrahim E, Hollender E, et al. Tuberculosis recurrence: multivariate analysis of serum levels of tuberculosis drugs, human immunodeficiency virus status, and other risk factors. Clin Infect Dis. 2001;32(3):515–7.
  15. Chideya S, Winston CA, Peloquin CA, Bradford WZ, Hopewell PC, Wells CD, et al. Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. Clin Infect Dis. 2009;48(12):1685–94.
  16. Van Tongeren L, Nolan S, Cook VJ, FitzGerald JM, Johnston JC. Therapeutic drug monitoring in the treatment of tuberculosis: a retrospective analysis. Int J Tuberc Lung Dis. 2013;17(2):221–4.
  17. Babalik A, Babalik A, Mannix S, Francis D, Menzies D. Therapeutic drug monitoring in the treatment of active tuberculosis. Can Respir J. 2011;18(4):225–9.
  18. Heysell SK, Moore JL, Keller SJ, Houpt ER. Therapeutic drug monitoring for slow response to tuberculosis treatment in a state control program, Virginia, USA. Emerg Infect Dis. 2010;16(10):1546–53.
  19. Holland DP, Hamilton CD, Weintrob AC, Engemann JJ, Fortenberry ER, Peloquin CA, et al. Therapeutic drug monitoring of antimycobacterial drugs in patients with both tuberculosis and advanced human immunodeficiency virus infection. Pharmacotherapy. 2009;29(5):503–10.
  20. Um SW, Lee SW, Kwon SY, Yoon HI, Park KU, Song J, et al. Low serum concentrations of anti-tuberculosis drugs and determinants of their serum levels. Int J Tuberc Lung Dis. 2007;11(9):972–8.
  21. Perlman DC, Segal Y, Rosenkranz S, Rainey PM, Remmel RP, Salomon N, et al. The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with tuberculosis. Clin Infect Dis. 2005;41(11):1638–47.
  22. Kimerling ME, Phillips P, Patterson P, Hall M, Robinson CA, Dunlap NE. Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients. Chest. 1998;113(5):1178–83.
  23. Burhan E, Ruesen C, Ruslami R, Ginanjar A, Mangunnegoro H, Ascobat P, et al. Isoniazid, rifampin, and pyrazinamide plasma concentrations in relation to treatment response in Indonesian pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2013;57(8):3614–9.
  24. Pasipanodya J, Gumbo T. An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future. Antimicrob Agents Chemother. 2011;55(1):24–34.
  25. Dickinson JM, Aber VR, Mitchison DA. Bactericidal activity of streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide alone and in combination against Mycobacterium Tuberculosis. Am Rev Respir Dis. 1977;116(4):627–35.
  26. Bottger EC. The ins and outs of Mycobacterium tuberculosis drug susceptibility testing. Clin Microbiol Infect. 2011;17(8):1128–34.
  27. Weiner M, Burman W, Vernon A, Benator D, Peloquin CA, Khan A, et al. Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine. Am J Respir Crit Care Med. 2003;167(10):1341–7.
  28. Weiner M, Benator D, Burman W, Peloquin CA, Khan A, Vernon A, et al. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clin Infect Dis. 2005;40(10):1481–91.
  29. Mehta JB, Shantaveerapa H, Byrd RP, Jr., Morton SE, Fountain F, Roy TM. Utility of rifampin blood levels in the treatment and follow-up of active pulmonary tuberculosis in patients who were slow to respond to routine directly observed therapy. Chest. 2001;120(5):1520–4.
  30. Steingart KR, Jotblad S, Robsky K, Deck D, Hopewell PC, Huang D, et al. Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis. 2011;15(3):305–16.
  31. Gallicano K, Khaliq Y, Carignan G, Tseng A, Walmsley S, Cameron DW. A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 2001;70(2):149–58.
  32. Goutelle S, Bourguignon L, Maire PH, Van Guilder M, Conte JE, Jr., Jelliffe RW. Population modeling and Monte Carlo simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of rifampin in lungs. Antimicrob Agents Chemother. 2009;53(7):2974–81.
  33. van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, et al. Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment?. Clin Infect Dis. 2011;52(9):e194–9.
  34. Peloquin CA, Jaresko GS, Yong CL, Keung AC, Bulpitt AE, Jelliffe RW. Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide. Antimicrob Agents Chemother. 1997;41(12):2670–9.
  35. McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P. Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrob Agents Chemother. 2006;50(4):1170–7.
  36. Kinzig-Schippers M, Tomalik-Scharte D, Jetter A, Scheidel B, Jakob V, Rodamer M, et al. Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrob Agents Chemother. 2005;49(5):1733–8.

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